U.S. patent application number 16/476025 was filed with the patent office on 2019-12-12 for branched polymeric biguanide compounds and their uses.
The applicant listed for this patent is HWANG-HSING CHEN. Invention is credited to HWANG-HSING CHEN.
Application Number | 20190373895 16/476025 |
Document ID | / |
Family ID | 62791413 |
Filed Date | 2019-12-12 |
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United States Patent
Application |
20190373895 |
Kind Code |
A1 |
CHEN; HWANG-HSING |
December 12, 2019 |
BRANCHED POLYMERIC BIGUANIDE COMPOUNDS AND THEIR USES
Abstract
Biocidal branched polymeric biguanide compounds are made by
polycondensation of sodium dicyanamide and a Afunctional primary
amine and/or a tetrafunctional primary amine and optionally with a
difunctional primary amine. The branched polymeric biguanide
compounds have 2-dimensional conformation that provides better
coverage over the surfaces of microorganisms and enhances efficacy
as biocides as compared to most commercially available linear
(one-dimensional) polymeric biguanide compounds. The bulkier
2-dimensional conformation of this invention limits the uptake,
accumulation and release of these branched polymers to and from
contact lenses. Therefore, these branched biguanide polymers can
reduce the cytotoxicity, enhance compatibility and suitable for
ophthalmic use. The highly branched polymers can be prepared with
minimum or no difunctional primary amines. The lightly branched
polymers can be prepared with of a minimum ratio of trifunctional
plus multifunctional primary amines to difunctional primary
amines.
Inventors: |
CHEN; HWANG-HSING; (ALLEN,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHEN; HWANG-HSING |
ALLEN |
TX |
US |
|
|
Family ID: |
62791413 |
Appl. No.: |
16/476025 |
Filed: |
December 20, 2017 |
PCT Filed: |
December 20, 2017 |
PCT NO: |
PCT/US2017/067678 |
371 Date: |
July 3, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62498580 |
Jan 3, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A01N 47/44 20130101;
A61K 47/34 20130101; C08G 73/065 20130101; C11D 3/0078 20130101;
A61K 2800/524 20130101; A61K 9/0048 20130101; A61K 8/84 20130101;
C11D 3/48 20130101 |
International
Class: |
A01N 47/44 20060101
A01N047/44; A61K 47/34 20060101 A61K047/34; A61K 8/84 20060101
A61K008/84; C08G 73/06 20060101 C08G073/06; A61K 9/00 20060101
A61K009/00 |
Claims
1. A biocide solution comprise a polymer having at least one of
branched biguanide units of the following formula: ##STR00010##
wherein Linker3+ represent linkage group with 3, or 4 points of
connections for biguanide groups and at least 1% of Linkers has 3
or 4 connections; Linker2+ represent independently the same or
different linkage groups with 2, 3, or 4 points of connections for
biguanide groups; Linkers represent the sum of Linker3+ and
Linker2+; Linkers represent synthetic/non-natural linkage groups
and has a molecular weight of less than 1000; l, m, n represent
integer varying from 1 to 100.
2. A biocide solution comprise a polymer according to claim 1
having at least one of branched biguanide units of the following
units: ##STR00011## wherein Linker4 represent linkage group with 4
points of connections for biguanide groups and at least 1% of
Linkers has 4 points of connections in Formular 2; Linker3
represent linkage group with 3 points of connections for biguanide
groups and at least 1% of the Linkers has 3 or more connections in
Formular 3; Linker2 represent independently the same or different
linkage groups with 2 points of connections for biguanide groups;
Linkers represent the sum of Linker4, Linker3, and Linker2; Linker4
independently represent Linker4 ##STR00012## Linker3 independently
represent Linker3 ##STR00013## Linker2 independently represent
Linker2 ##STR00014## l, m, n, o represent integer varying from 1 to
100.
3. A pharmaceutical composition comprising a preservation-effective
amount of a polymer according to claim 1.
4. A pharmaceutical composition comprising a preservation-effective
amount of a polymer according to claim 2.
5. A lens care composition comprising a disinfecting-effective
amount of a polymer according to claim 1.
6. A lens care composition comprising a disinfecting-effective
amount of a polymer according to claim 2.
7. An ophthalmic solution of claim 1, wherein the polymer has a
molecular weight adequate to ensure that it is not substantially
adsorbed onto and/or absorbed into hydrophilic contact lenses.
8. An ophthalmic solution of claim 2, wherein the polymer has a
molecular weight ranging from 500 to 100,000.
9. A biocide solution of claim 2, wherein the composition may
contain one or more additional antimicrobial agent, for example but
not limited to, polyhexamethylene biguanide polymers ("PHMB"),
polyquaternium-1, myristamidopropyl dimethylamine (Aldox), and
amino biguanides.
10. A biocide solution of claim 2, wherein the concentration of the
polymer in the ophthalmic solution ranges from 0.0001 to 3.0 w/v
%.
11. A cosmetic composition comprising a preservation-effective
amount of a polymer according to claim 1.
12. A cosmetic composition comprising a preservation-effective
amount of a polymer according to claim 2.
13. A method for preparation of a branched polymer according to
claim 2 by a process of: a) mixing metal dicyanoamide,
trifunctional amine and acid, optionally with difunctional amine,
b) isolating branched polybiguanide by ultrafiltration or
precipitation, wherein difunctional amines are selected from the
groups consisting of hexane-1,6-diamine, pentane-1,5-diamine,
butane-1,4-diamine, propane-1,3-diamine, ethane-1,2-diamine, and
heptane-1,7-diamine; trifunctional amines are selected from the
groups consisting of propane-1,2,3-triamine,
pentane-1,3,5-triamine,
N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamin-
e, and
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-tr-
iamine; metal dicyanoamide are selected from the groups consisting
of lithium dicyanoamide, sodium dicyanoamide, potassium
dicyanoamide, and calcium dicyanoamide; acid are selected from the
groups consisting of hydrochloric acid, hydrobromic acid and
sulfuric acid.
14. A method for preparation of a branched polymer according to
claim 2 by a process of: a) mixing di(cyanguanido)alkane,
trifunctional amine and acid, optionally with difunctional amine,
b) isolating branched polybiguanide by ultrafiltration or
precipitation, wherein di(cyanguanido)alkane are selected from the
groups consisting of 1,6-di(N.sup.3-cyano-N.sup.1-guanidino)hexane,
1,5-di(N.sup.3-cyano-N.sup.1-guanidino)pentane,
1,4-di(N.sup.3-cyano-N.sup.1-guanidino)butane and
1,3-di(N.sup.3-cyano-N.sup.1-guanidino)propane; difunctional amines
are selected from the groups consisting of hexane-1,6-diamine,
pentane-1,5-diamine, butane-1,4-diamine, propane-1,3-diamine,
ethane-1,2-diamine, and heptane-1,7-diamine; trifunctional amines
are selected from the groups consisting of propane-1,2,3-triamine,
pentane-1,3,5-triamine,
N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamin-
e, and
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-tr-
iamine; acid are selected from the groups consisting of
hydrochloric acid, hydrobromic acid and sulfuric acid.
15. A method for preparation of a branched polymer according to
claim 2 by a process of: a) mixing polyhexanide, trifunctional
amine, and acid, optionally with difunctional amine and/or
di(cyanguanido)alkane, b) isolating branched polybiguanide by
ultrafiltration or precipitation, wherein di(cyanguanido)alkane are
selected from the groups consisting of
1,6-di(N.sup.3-cyano-N.sup.1-guanidino)hexane,
1,5-di(N.sup.3-cyano-N.sup.1-guanidino)pentane,
1,4-di(N.sup.3-cyano-N.sup.1-guanidino)butane and
1,3-di(N.sup.3-cyano-N.sup.1-guanidino)propane; difunctional amines
are selected from the groups consisting of hexane-1,6-diamine,
pentane-1,5-diamine, butane-1,4-diamine, propane-1,3-diamine,
ethane-1,2-diamine, and heptane-1,7-diamine; trifunctional amines
are selected from the groups consisting of propane-1,2,3-triamine,
pentane-1,3,5-triamine,
N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamin-
e, and
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-tr-
iamine; acid are selected from the groups consisting of
hydrochloric acid, hydrobromic acid and sulfuric acid.
16. A method for preparation of a branched polymer according to
claim 2 by a process of: a) mixing metal dicyanoamide,
trifunctional amine, acid, and isolating intermediate, b) reacting
with difunctional amine, optionally with di(cyanguanido)alkane, c)
isolating branched polybiguanide by ultrafiltration or
precipitation; wherein di(cyanguanido)alkane are selected from the
groups consisting of 1,6-di(N.sup.3-cyano-N.sup.1-guanidino)hexane,
1,5-di(N.sup.3-cyano-N.sup.1-guanidino)pentane,
1,4-di(N.sup.3-cyano-N.sup.1-guanidino)butane and
1,3-di(N.sup.3-cyano-N.sup.1-guanidino)propane; difunctional amines
are selected from the groups consisting of hexane-1,6-diamine,
pentane-1,5-diamine, butane-1,4-diamine, propane-1,3-diamine,
ethane-1,2-diamine, and heptane-1,7-diamine; trifunctional amines
are selected from the groups consisting of propane-1,2,3-triamine,
pentane-1,3,5-triamine,
N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamin-
e, and
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-tr-
iamine; metal dicyanoamide are selected from the groups consisting
of lithium dicyanoamide, sodium dicyanoamide, potassium
dicyanoamide, and calcium dicyanoamide; acid are selected from the
groups consisting of hydrochloric acid, hydrobromic acid and
sulfuric acid.
Description
CROSS-REFERENCE TO RELATED APPLICATION
Field of Invention
[0001] The present invention relates to biocidal branched polymers
comprising polymeric biguanide. The branched polymeric biguanide
are made by polycondensation of sodium dicyanamide and a
trifunctional and/or a tetrafunctional primary amine and optionally
with a difunctional primary amine to control the number of
branches. The branched polymeric biguanide can also be made by
polycondensation of guanidine hydrochloride and a trifunctional
and/or a tetrafunctional primary amine and optionally with a
difunctional primary amine to control the number of branches. The
preferred tetrafunctional primary amines include
3,3',3'',3''-(ethane-1,2-diylbis(azanetriyl))tetrakis(N-(2-aminoethyl)pro-
panamide),
N1,N1'-(ethane-1,2-diyl)bis(N1-(3-aminopropyl)propae-1,3-diamin-
e), and
N2,N2'-(propane-1,3-diyl)bis(N4,N6-bis(3-aminopropyl)-1,3,5-triazi-
ne-2,4,6-triamine). The preferred trifunctional primary amines
include propane-1,2,3-triamine, pentane-1,3,5-triamine,
N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine-
,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamin-
e,
N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-triami-
ne. The preferred difunctional primary amines include
hexane-1,6-diamine, pentane-1,5-diamine, butane-1,4-diamine,
propane-1,3-diamine, ethane-1,2-diamine, heptane-1,7-diamine.
[0002] The branched polymers exhibit higher biocidal efficacy
especially against algae and fungi presumably because of the better
surface coverage of the microorganisms. The branched polymers
exhibit higher molecular weight as compared to non-branched
(linear) polymers and have higher biocidal efficacy. The branched
polymers have 2-dimensional network and can improve compatibility
with sensitive tissues and are highly safe for the eyes and skin,
and have a negligible adsorption onto contact lenses and suitable
for ophthalmic and cosmetic uses.
Background Art
[0003] A biocide is a chemical substance, which can deter, render
harmless, or exert a controlling effect on any harmful organism.
Biocides are commonly used in medicine, agriculture, forestry, and
industry.
[0004] The development of new and useful biocides requires
consideration of many elements such as the following: the type of
organism whose control is desired; the manner in which the biocide
is to be deployed; the costs of preparing and delivering the
biocide; environmental or disposal issues; and so on. Depending on
the potential use envisioned, primary considerations are likely to
include both its potency against the organisms targeted, as well as
its biocompatibility, e.g. lack of toxicity against the humans or
animals which may come into contact with it. Biocides may have a
broad or narrow spectrum of activity.
[0005] Many of the current organic biocides have two functional
group components, a hydrophilic/polar part and a hydrophobic/oil
part. Broad-spectrum biocides may require higher hydrophobic
elements in order to penetrate biological membranes and achieve
their full potency. Hydrophobicity in biocides can be achieved
through incorporation of long chain hydrocarbons or aryl groups
into the structure of the molecule. However, the current organic
biocides used in the pharmaceutical field are focused on improving
biocompatibility to reduce the toxicity against human tissues.
Discovery of biocides with a desired balance between hydrophilicity
and hydrophobicity for its field of use is important and highly
challenging.
[0006] Polyhexamethylene biguanide (PHMB) is one of the most common
and potent biocide being used in the ophthalmic solution and
cosmetic application. Although higher MW is necessary for higher
efficacy, the average polymer length of PHMB is only about 5
(Journal of Applied Bacteriology 1990, 69, p 593-598) or 12
(British Journal of Environmental Sciences Vol. 4, No 1, pp. 49-55,
February 2016). The small molecule of PHMB facilitates penetration
and accumulation readily into contact lens or skin and causes
irritation when worn in the eye or applied on skin.
[0007] For their potential in overcoming some of the disadvantage
of the smaller organic monomeric biguanide compound described
above, polymeric bigunide compounds has been investigated for a
number of years.
[0008] For example, U.S. Pat. No. 9,492,771 B2 discloses
"Polyethtyleneimine and polyalkylene biguanide ligand graft
functionalized substrates" are useful in selectively binding and
removing biological materials, such as viruses, from biological
samples.
[0009] WO 99/24542 discloses polyhexamethylene biguanide with
alkylamine capping groups at the two ends of the polymer.
[0010] WO 2017/163091 A1, WO 2015/044669 A1, WO 2013/054123 A1
disclose a composition for use in the treatment of fungal infection
comprising a polymer/nanoparticle with linear or branched backbone
that has terminal monoguanide, guanidine and biguanide groups.
[0011] WO 2017/141,204 A2 discloses an entry-promoting agent
comprises a liner and/or branched dendrimeric polymer with
grafted/crosslinked biguanidine moieties.
[0012] U.S. Pat. No. 9,278,079 discloses an ocular composition
consisting polyhexamethylene biguanide. The composition can be
applied to a fabric pad for use as an eyelid cleanser, where the
fabric pad is pre-moistened with the composition and packaged for
use. The composition may also be used in an eyelid treatment kit
for convenient combination treatments to improve overall eyelid
hygiene and adjunctive eyelid therapy.
[0013] WO 2012/047630 A2 discloses uses of linear or branched
polymer with guanide, biguanide or phenylguanide as capping groups
for anti-bacterial/HIV infection.
[0014] WO 00/35862, WO99/24542, U.S. Pat. Nos. 8,440,212,
7,951,387, 6,503,952, 6,303,557, 6,010,687, 5,922,693, 5,885,562,
5,668,084, 5,529,713, 5,470,875, 5,356,555, and 5,141,803 disclose
compositions consisting of polyhexamethylene biguanide for
antimicrobial, wound dressing, cleaning and deodorant uses.
[0015] U.S. Pat. No. 5,453,435 discloses a preservative system
consisting of polyhexamethylene biguanide for use in contact lens
solutions.
[0016] However, polyhexamethylene biguanide is known to be
irritating to ocular tissues. All of the prior art are related to
linear polymeric biguande compounds and compositions but none of
branched polymeric biguanide compounds are disclosed. There still
exists a need for biocides with useful antimicrobial activity;
non-irritating; low toxicity; compatibility with the materials and
tissue with which they come into contact.
SUMMARY OF THE INVENTION
[0017] The present invention is directed to branched polymeric
biguanide compounds. In particular, this invention relates to new
polymeric biguanide compounds, which contain branched biguanide
groups with 2-dimentional networks for the maximal surface coverage
of the microorganisms to enhance antimicrobial efficacy and for
minimal uptake, accumulation and release of contact lenses to
enhance ocular safety. The present invention also relates to the
use of these compounds as biocide in the industry, especially in
pharmaceutical, cosmetic and lens care products. In particular, the
present invention relates to the use of these new compounds as
preservatives for ophthalmic, otic, cosmetic or nasal compositions
and as disinfectants for contact lens care products.
[0018] The compounds of the present invention differ from prior
compounds through the introduction of branched biguanide groups.
Without wishing to be bound by theory, it is thought that the
branched biguanide groups may increase antimicrobial efficacy by
maximal surface coverage with the two dimensional conformation and
enhance ocular comfort by minimum uptake and release on contact
lenses. Other features and advantages of the invention will become
apparent from the following detailed description and claims.
DESCRIPTION OF THE INVENTION
[0019] The novel biocides of this invention comprise a polymer
having at least one of branched biguanide units of the following
formula:
##STR00001##
wherein Linker3+ represent linkage group with 3, or 4 points of
connections for biguanide groups and at least 1% of the Linkers has
3 or 4 connections; Linker2+ represent independently the same or
different linkage groups with 2, 3, or 4 points of connections for
biguanide groups; Linkers represent the sum of Linker3+ and
Linker2+; Linkers represent synthetic/non-natural linkage groups
and has a molecular weight of less than 1000; l, m, n represent
integer varying from 1 to 100, preferably from 1 to 20.
[0020] The preferred biocides of the present invention comprise a
branched biguanide polymer of the following units:
##STR00002##
wherein Linker4 represent linkage group with 4 points of
connections for biguanide groups and at least 1% of the Linkers has
4 points of connections in Formular 2; Linker3 represent linkage
group with 3 points of connections for biguanide groups and at
least 1% of the Linkers has 3 or more connections in Formular 3;
Linker2 represent independently the same or different linkage
groups with 2 points of connections for biguanide groups; Linkers
represent the sum of Linker4, Linker3 and Linker2; Linker4
independently represent
[0021] Linker4
##STR00003##
Linker3 independently represent
[0022] Linker3
##STR00004##
Linker2 independently represent
[0023] Linker2
##STR00005##
l, m, n, o represent integer varying from 1 to 100, preferably from
1 to 20.
[0024] The preferred branched units of the present invention are
exampled in but not limited to the following examples;
Example 1
##STR00006##
[0025] Example 2
##STR00007##
[0027] The biocides of the present invention have broad spectrum of
antimicrobial activity and can be used in many applications
including ophthalmic solutions. The ophthalmic solutions of the
present invention can be formulated in various compositions,
particularly as disinfectants in contact lens care products and as
preservatives in cosmetic, ophthalmic, nasal or otic compositions,
and are especially suitable for use in ophthalmic compositions such
as artificial tears or topical ophthalmic pharmaceutical
preparations. The types of compositions which may be preserved by
the compounds of formula (I) include: ophthalmic pharmaceutical
compositions, such as those described below; otic pharmaceutical
compositions, such as topical compositions used in the treatment of
bacterial infections or inflammation of the ear; dermatological
compositions, such as anti-inflammatory compositions, as well as
shampoos and other cosmetic compositions; and various other types
of pharmaceutical compositions. In general, the polymers of the
present invention will be present in the compositions at a
concentration between about 0.00001 and 1.0 percent by
weight/volume percent (w/v %). If used as a disinfectant, the
polymers are preferably present at a concentration of between about
0.0005 and 0.5 w/v %; if used as a preservative; the polymers are
present at a concentration between about 0.00005 and 0.05 w/v %. It
is preferred that the polymers are present at a concentration of
between 0.001 and 0.05 w/v % if used as a disinfectant and between
0.0001 and 0.01 w/v % if used as a preservative.
[0028] The compositions of the present invention may additionally
contain other components, for example, buffers, tonicity adjusting
agents, chelating agents, surfactants, solubilizers, active
pharmaceutical agents, preservatives, pH adjusting agents and
carriers.
[0029] In the case of contact lens and ophthalmic solutions, for
example, various agents are added to enhance compatibility with the
eye. To avoid stinging or irritation it is important that the
solution possess a tonicity and pH within the physiological range,
e.g., 200-350 mOsmole for tonicity and 6.5-8.5 for pH. To this end,
various buffering and osmotic agents are often added. The simplest
osmotic agent is sodium chloride since this is a major solute in
human tears. In addition propylene glycol, lactulose, trehalose,
sorbitol, mannitol or other osmotic agents may also be added to
replace some or all of the sodium chloride. Also, various buffer
systems such as citrate, phosphate (appropriate mixtures of
Na.sub.2HPO.sub.4, NaH.sub.2PO.sub.4, and KH.sub.2PO.sub.4), borate
(boric acid, sodium borate, potassium tetraborate, potassium
metaborate and mixtures), bicarbonate, and tromethamine and other
appropriate nitrogen-containing buffers (such as ACES, BES, BICINE,
BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS,
PIPES, TAPS, TES, Tricine) can be used to ensure a physiologic pH
between about pH 6.5 and 8.5. Borate and polyol systems may also be
used to provide buffering, to enhance antimicrobial activity, or to
provide both buffering and an enhancement of antimicrobial
activity, or other useful properties to the compositions of the
invention. The borate and polyol systems, which may be used,
include those described in U.S. Pat. Nos. 6,849,253; 6,503,497;
6,365,636; 6,143,799; 5,811,466; 5,505,953; and 5,342,620; the
entire contents of each are hereby incorporated into the present
specification by reference.
[0030] The borates, which may be used in the compositions of the
present invention, include boric acid and other pharmaceutically
acceptable salts such as sodium borate (borax) and potassium
borate. As used herein, the term "borate" refers to all
pharmaceutically suitable forms of borates, as well as metaborates.
Borates are common excipients in ophthalmic formulations due to
good buffering capacity at physiological pH and well-known safety
and compatibility with wide range of drugs and preservatives.
[0031] In addition to the compounds of formula (1, 2, 3, and 4)
described above, the compositions of the present invention may
contain one or more additional antimicrobial agent. The invention
is not limited relative to the types of additional antimicrobial
agent that may be utilized. The preferred biocides include:
polyhexamethylene biguanide polymers ("PHMB"), polyquaternium-1,
and the amino biguanides described in U.S. Pat. No. 6,664,294, the
entire contents of which are hereby incorporated in the present
specification by reference.
[0032] Amidoamines, amino alcohols, and borate/polyol complexes may
also be utilized to enhance the antimicrobial activity of the
compositions described herein. The preferred amidoamines are
myristamidopropyl dimethylamine ("MAPDA") and related compounds
described in U.S. Pat. No. 5,631,005 (Dassanayake, et al.). The
preferred amino alcohols are 2-amino-2-methyl-1-propanol ("AMP")
and other amino alcohols described in U.S. Pat. No. 6,319,464
(Asgharian). The entire contents of the '005 and '464 patents are
hereby incorporated in the present specification by reference.
[0033] The following schemes further illustrate certain embodiments
of the invention. These examples are provided to aid in the
understanding of the invention and are not to be construed as
limitations thereof.
##STR00008##
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[0034] The polymer with the formula 2 was obtained by a synthetic
method described below.
[0035] Compound 1. A mixture of tris(2-aminoethyl)amine-3HCl (0.256
g, 1.0 mmol, 0.217 eq),
1,6-di(N.sup.3-cyano-N.sup.1-guanidino)hexane (1.15 g, 4.60 mmol,
1.0 eq), hexane-1,6-diamine-2HCl (0.567 g-0.1 g, 3.00 mmol, 0.65
eq) in 2-ethoxyethanol (3 mL) was heated at 165.degree. C. for 10
min and 175.degree. C. for 2 h. The milky suspension was added
hexane-1,6-diamine-2HCl (0.1 g) and heated at 155 C overnight. The
mixture was cooled and turned into a two-layer liquid. The mixture
was heated at 175.degree. C. and monitored by NMR until the
starting material disappeared. The solvent was distilled out and
the residue was placed into vacuum to give a foamy-gummy solid. The
solid was mixed with MeOH (4 mL) and precipitated with acetone to
give a gum that was dried in vacuum to give the desired compound as
foamy solid. NMR spectrum confirmed the structure of the
product.
[0036] Compound 2. A mixture of tris(2-aminoethyl)amine-3HCl (0.23
g, 0.90 mmol, 0.82 eq),
1,6-di(N.sup.3-cyano-N.sup.1-guanidino)hexane (0.60 g, 2.4 mmol,
2.18 eq), polyhexanide (2.00 g, 1.10 mmol, 1.0 eq) was heated at
150 C for 3 h under nitrogen and tuned into a solid. The solid was
crashed into powder, mixed with 2-methoxyethanol (3 mL) and was
heated at 175.degree. C. and monitored by NMR until the starting
material disappeared. The solvent was evaporated by heating at
185.degree. C. and the residue was dried in vacuum to give glassy
solid. NMR spectrum confirmed the structure of the product.
[0037] Compound 3. A mixture of tris(2-aminoethyl)amine-3HCl (0.35
g, 1.37 mmol, 1.25 eq),
1,6-di(N.sup.3-cyano-N.sup.1-guanidino)hexane (0.60 g, 2.4 mmol,
2.18 eq), polyhexanide (2.00 g, 1.10 mmol, 1.0 eq) was heated at
150 C for 3 h under nitrogen and tuned into a solid. The solid was
crashed into powder, mixed with 2-methoxyethanol (3 mL) and was
heated at 175.degree. C. and monitored by NMR until the starting
material disappeared. The solvent was evaporated by heating at
185.degree. C. and the residue was dried in vacuum to give glassy
solid. NMR spectrum confirmed the structure of the product.
[0038] The antibacterial effectiveness testing of these samples and
2 standards was done against C. alibicans (ATCC 10231) as shown
below.
TABLE-US-00001 C. albicans ATCC 10231 Log Log Sample ID Calculated
Log Recovery Reduction Polyhexanide A 1 ppm 5.0 <1.0 >4.0
Polyhexanide B 1 ppm 5.0 1.5 3.5 Compound 1 1 ppm 5.0 2.0 3.0
Compound 2 1 ppm 5.0 2.5 2.5 Polyhexanide A 5 ppm 5.0 1.5 3.5
Polyhexanide B 5 ppm 5.0 1.0 4.0 Compound 1 5 ppm 5.0 <1.0
>4.0 Compound 2 5 ppm 5.0 <1.0 >4.0
* * * * *